Over the summer, Chicago-based cardiologist Dr. Sandeep Nathan received a phone call that a patient was in trouble.
Every minute that went by put the patient more at risk. In his mid-30s, he was suffering from a massive heart attack with excessive blood clotting in the vessels around his heart. He had also tested positive for Covid-19.
Several studies have shown that coronavirus impacts more than just the lungs and respiratory system – including the heart. “There is an acute inflammatory response, increased blood clotting and cardiac involvement,” cardiologist Dr. Nieca Goldberg, medical director of New York University’s Women’s Heart Program, previously told CNN Health. Goldberg is also a senior adviser for women’s health strategy at NYU Langone Health.
Before beginning a procedure to clear the vessels and put in stents, Nathan and his team administered blood thinners, including Integrilin, to help break up the clots.
The US Food and Drug Administration first approved Integrilin in 1998, and medical professionals commonly prescribe it to heart attack patients. But what many people don’t realize is the drug was originally derived from a protein found in the venom of the pygmy rattlesnake.
“Several hundred thousand heart attacks occur in the United States every year, and a significant proportion of these heart attacks are treated with agents, which unbeknownst to both the physician and patient, are actually derived from animal venom,” said Nathan, director of the University of Chicago Medicine’s Coronary Care Unit and co-director of its Cardiac Catheterization Lab.
“There’s a bit of a misconception that drug development, particularly with antiplatelets or anticoagulants, is now passé – that we’ve discovered everything that we need to know,” he added. “In my opinion, nothing could be further from the truth.”
Creating ‘designer toxins’
Roughly a decade ago, Nathan received a call from biomedical scientist Zoltan Takacs, who expressed they had a “mutual interest.”
“We were approaching (venom-derived) compounds from two very different vantage points,” Nathan remembered Takacs telling him. “He wanted to discuss possibilities for academic collaboration and education.”
While Nathan administers the venom-derived drugs to his patients, Takacs is on the other end of the process – finding the original sources in the field: the venomous creatures themselves.
“What makes these creatures like a gold mine for medicine is actually the deadliness,” Takacs recently told CNN’s Dr. Sanjay Gupta. Toxins, he added, have been “tweaked by nature to take a life” with utmost efficiency.
“They aim (for) critical parts of the body, like the nervous function or the blood circulation. Those are the systems which you have to take under control in order to treat many different types of diseases.”
While the pandemic has slowed his usually hectic travel schedule – Takacs said he has visited more than 190 countries in his lifetime so far – his work continues through his partners in the field and in the lab.
He is the co-inventor of the Designer Toxins drug discovery platform, and founder of ToxinTech, a biotech startup that houses a library of “designer toxins,” available to researchers studying drug development.
“We’re actually not only creating toxin libraries, we’re doing a twist,” Takacs explained. “If we have a target for which there is not a good molecule which blocks that target, for example, then we look (to) nature. What kind of toxins around the world exist which target that particular molecule?”
In the lab, Takacs “chops up” the toxins into “bits and pieces” with genetic engineering, and rearranges the parts in every possible combination to create “mosaic toxins.” These variants still contain the “evolutionary wisdom,” he said, but differ slightly in biological activity.
“Then you screen this huge library to see which is the best match against the target of interest,” he said, in whatever disease you’re trying to treat.
From there, “it evolves into a drug lead and animal trials – and hopefully, in the long run, into clinical trials” with human participants.
The toxins can be replicated in the lab, meaning samples are not needed from the venom-producing animals every time. Exenatide, an FDA-approved drug used to treat Type 2 diabetes, for example, comes from the venom of the Gila monster – and is synthetically reproduced.
Takacs said his latest research includes potential targets for Parkinson’s disease, cancer and gene therapy.
Looking to nature
Even before the coronavirus pandemic, the search for new sources to become drug therapies had taken on greater urgency with the rise of antibiotic-resistant “superbugs” – declared “one of the top 10 global public health threats facing humanity” by the World Health Organization.
Researchers are increasingly turning to nature – including the fjords of the Norwegian arctic, an ancient medieval natural remedy and the dirt under your feet – for new bacteria to become antibiotics.
Nature also inspired the Nobel Prize-winning Chinese scientist Tu Youyou, who was recognized for her work on a malaria therapy. Inspired by ancient texts on herbal remedies in traditional Chinese medicine, she found that wormwood had been used to treat severe fever and extracted a substance called artemisinin, the basis for several malaria drugs.
References to venom as medical treatments also go back hundreds, if not thousands, of years. But it wasn’t until 1981 that the first FDA-approved, venom-derived medication hit the market, opening the door for a completely new class of medication, Takacs said.
Captopril was also the first approved drug in a class known as angiotensin-converting enzyme inhibitors, which help relax blood vessels and lower blood pressure. In fact, ACE inhibitors are now used to treat tens of millions of patients worldwide, and Captopril is widely prescribed for hypertension, or high blood pressure.
Its original source? The venom of the Brazilian pit viper, which causes a sudden drop in blood pressure in its prey.
“Toxins are good for so many different types of diseases, because there are so many of them in nature,” explained Takacs. “We have 150,000 venomous species combined. They have 20 million toxins, and 99.9% of the 20 million toxins in nature are unexplored.”
It’s that untapped potential that Takacs finds most promising, and that Nathan sees as critical for his cardiology patients, considering the current circumstances.
“I think the current pandemic that we’re in with Covid-19 and all of the coagulation-associated abnormalities has underscored the need for cleaner and more targeted anticoagulants,” Nathan said. “And this is only going to continue in the future.”